Epidemiologic evidence has identified unopposed estrogen exposure as a risk factor associated with endometrial carcinogenesis. A significant proportion of endometrial adenocarcinomas express immunohistochemically detectable estrogen (ER) and progesterone (PR) receptors and objective clinical responses to "antiestrogenic" therapy using progestational agents (Megace TM) are well documented. The availability of SERMs that exhibit tissue-specific agonist or antagonist profiles now permits a more targeted approach to interference with (ER) signaling. One of these SERMs, LY353381 (Arzoxifene TM)developed by Eli Lilly, has been shown to function as an antagonist in the uterus in preclinical studies, although the molecular mechanisms responsible for this antagonism are unknown. Two small phase II trials have shown a response rate to Arzoxifene TM of >30% among women with receptor positive metastatic disease. We propose to perform a multi-institutional trial of Arzoxifene TM in women with advanced or recurrent endometrial adenocarcinoma and to combine these clinical investigations with laboratory-based studies to identify potential mechanisms of action of this SERM. In Specific Aim 1 we will conduct a clinical trial to determine the objective clinical response rate to Arzoxifene TM in women with endometrial adenocarcinoma and measure time to progression, response duration and survival for treated patients. In Specific Aim 2, to identify potential biomarkers of SERM efficacy, we will characterize ER, PR and TGFbeta signaling pathways in patient material from the clinical trial to correlate tumor phenotype with response to Arzoxifene TM. Additional experiments will be performed using primary cultures of normal and neoplastic endometrial cells to identify the mechanism(s) by which Arzoxifene TM functions as an antagonist in these cells. In Specific Aim 3, transcriptional profiles obtained with microarrays will be used to identify key "agonist marker genes" specifically induced in endometrial cells in response to agonists (E2 and tamoxifen) and test the hypothesis that antagonism is due to the inability of SERMs such as Arzoxifene TM to induce the expression of these genes. In addition, a molecular profile will be generated of coactivators and corepressors recruited by the ER when liganded to antagonists (Arzoxifene TM) versus agonists (tamoxifen and E2) to identify the mechanism underlying antagonism by SERMs such as Arzoxifene TM at specific gene loci. Completion of the clinical trial will substantiate the effectiveness of SERMs as therapeutic agents and laboratory correlates performed in conjunction with this trial will provide insight into the molecular mechanism of antagonism of Arzoxifene TM in endometrial carcinoma, and potentially, biomarkers of efficacy that will be valuable in future clinical studies.